Impact of SGLT2 inhibitors on cardiac fibroblasts properties

Clinical trials conducted over the past five years have reported significant cardioprotection conferred by antidiabetic SGLT2 inhibitors, including Cana-, Empa- and Dapagliflozin. These drugs showed significant reduction in hospitalizations and death for heart failure with reduced and preserved ejection fraction, in both diabetic and non-diabetic patients. The mechanisms underlying these protective effects cannot be fully explained by glucose lowering properties and remain poorly understood. We investigated the impact of SGLT2 inhibitors on cardiac fibroblasts properties, namely proliferation and myodifferentiation. For proliferation assessment, cultured human cardiac fibroblasts (HCFs) were serum starved for 24 h prior to stimulation with 1% fetal bovine serum and 1, 3 or 10 μM of Cana-, Empa- or Dapagliflozin. Proliferation was measured by flow cytometry, using 5-ethynyl-2′-deoxyuridine. To assess myodifferentiation, HCFs were serum starved for 2 h before stimulation with 1, 3 or 10 μM of Cana-, Empa- or Dapagliflozin for 72 hours. Transforming growth factor-β1 (TGFβ1) was added at the time of stimulation, to induce HCFs myodifferentiation. Then, we measured expression levels of the myodifferentiation marker α-smooth muscle actin (αSMA) and collagen type I by RT-qPCR. All SGLT2 inhibitors did not affect HCFs proliferation. Empa- and Dapagliflozin led to a significant decrease of 50% in the expression of αSMA (P < 0.05) and collagen type I (P < 0.01), compared to control. However, Canagliflozin barely affected myodifferentiation. In contrast to Canagliflozin, Empa- and Dapagliflozin significantly reduced myodifferentiation of HCFs. Our results suggest that all SGLT2 inhibitors will not have the same impact on extracellular matrix remodeling. Accordingly, Empa- and Dapagliflozin could be more potent in preventing extracellular matrix remodeling and interstitial fibrosis in the context of heart failure.